A novel and practical synthesis of (+)-biotin via Fukuyama coupling reaction

作者：Shimizu T^*

来源：Journal of the Pharmaceutical Society of Japan, 2003, 123(2): 43-52.

DOI：10.1248/yakushi.123.43

• (+)-biotin
• thiolactone
• L-aspartic acid
• Fukuyama coupling reaction

(+)-Biotin (1) was synthesized from readily accessible L-aspartic acid (4). The contiguous asymmetric centers at C-3a and C-6a were formed through a diastereoselective aldol reaction of N-Cbz-3-amino-4-butanolide 5 to provide trans-disubstituted lactone 6 with high stereo selectivity (trans/cis = 12 : 1). The imidazolidin-2-one moiety of 1 was constructed by a stereoselective Hofmann rearrangement of beta-substituted asparagine derivative 7 to provide cyclic urea 8. This reaction proceeds with complete retention of stereochemistry. Removal of the protective groups of 8 and subsequent dibenzylation and thionation provided thiolactone 2. The installation of the C-4 side chain of 1 was performed through a Pd/C-catalyzed coupling reaction of 2 with ethoxycarbonylbutylzinc iodide 14a (Fukuyama coupling reaction), which permitted the synthesis of 1 from 2 under industrially applicable mild conditions in three steps.

• 出版日期2003-2